Abstract
Orexins are hypothalamic neuropeptides that were initially identified in the rat brain as endogenous ligands for an (previously) orphan G-protein-coupled receptor (GPCR). They are multitasking peptides involved in many physiological functions, including regulation of feeding behavior, wakefulness and autonomic/neuroendocrine functions, and sleep/wakefulness states in mammals. There are two isopeptides of orexin, orexin A and orexin B, which are produced from a common precursor peptide, prepro-orexin. Structures of orexins, as well as orexin genes, are highly conserved throughout mammalian species, suggesting strong evolutionary pressure that maintains the structures. Their lengths and structure suggested that orexin B is the ancestral form of the orexin neuropeptide. In mammals, orexins bind to two subtypes of GPCRs, i.e., orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R). Phylogenetically, the orexin system is present exclusively in vertebrates. In genomes of species outside mammals, there is only one orexin receptor, which is similar to OX2R, suggesting that OX2R is the prototype receptor for orexins. OX1R is likely to have evolved during early mammalian evolution. Orexin-producing neurons (orexin neurons) are mainly located in the lateral hypothalamic area (LHA) in mammals and are also found in hypothalamic regions in many other vertebrates. Orexins are likely to be closely related to the regulation of active, motivated behavior in many species. The orexin system seems to have evolved as a system that supports active and purposeful behavior which is closely related with wakefulness.
Highlights
Orexins were initially recognized as regulators of feeding behavior
We showed that orexin 1 receptor (OX1R) in noradrenaline neurons in the locus coeruleus (LC) plays a role in the expression and/or consolidation of cued fear memory by exciting these neurons that send innervations to the lateral amygdala (Soya et al, 2013)
Orexin fibers were shown to innervate the monoaminergic nuclei, including the dorsal raphe (DR), LC, mesopontine-like area, dopaminergic clusters, and histaminergic neurons in the tuberomammillary nucleus (TMN), showing resemblance to the mammalian orexin system (Kaslin and Panula, 2001; Huesa et al, 2005; Nakamachi et al, 2006; Amiya et al, 2007; Kojima et al, 2009). These findings suggest that orexin neurons are basically found in the hypothalamus and send rich projections to monoaminergic neurons
Summary
Orexins were initially recognized as regulators of feeding behavior. Subsequently, the finding that orexin deficiency causes narcolepsy in several mammalian species revealed that orexins play a critical role in regulation of sleep/wakefulness states, especially in maintenance of wakefulness in mammals. Mammalian orexin B is a 28-amino-acid, C-terminally amidated linear peptide, which has a highly conserved structure among mammalian species.
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